EP3632912B1 - Pyridoquinazoline derivatives useful as protein kinase inhibitors - Google Patents

Pyridoquinazoline derivatives useful as protein kinase inhibitors Download PDF

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EP3632912B1
EP3632912B1 EP18759146.6A EP18759146A EP3632912B1 EP 3632912 B1 EP3632912 B1 EP 3632912B1 EP 18759146 A EP18759146 A EP 18759146A EP 3632912 B1 EP3632912 B1 EP 3632912B1
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quinazoline
oxo
pyrido
carboxamide
branched
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EP3632912A1 (en
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Guido Kurz
Juan CAMACHO GÓMEZ
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Oncostellae SL
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Oncostellae SL
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Priority to RS20210545A priority Critical patent/RS61833B1/sr
Priority to SI201830289T priority patent/SI3632912T1/sl
Priority to PL18759146T priority patent/PL3632912T3/pl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24C—DOMESTIC STOVES OR RANGES ; DETAILS OF DOMESTIC STOVES OR RANGES, OF GENERAL APPLICATION
    • F24C7/00—Stoves or ranges heated by electric energy
    • F24C7/08—Arrangement or mounting of control or safety devices
    • F24C7/082—Arrangement or mounting of control or safety devices on ranges, e.g. control panels, illumination
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24C—DOMESTIC STOVES OR RANGES ; DETAILS OF DOMESTIC STOVES OR RANGES, OF GENERAL APPLICATION
    • F24C7/00—Stoves or ranges heated by electric energy
    • F24C7/08—Arrangement or mounting of control or safety devices
    • F24C7/087—Arrangement or mounting of control or safety devices of electric circuits regulating heat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to novel 11-oxo-11H-pyrido[2,1-b] quinazoline-6-carboxamide derivatives conveniently substituted as potent inhibitors of at least one protein kinase, especially a kinase selected from the group consisting of AMPK-related kinase ARK5 and Janus kinase JAK3 and Janus kinase TYK2.
  • Other objectives of the present invention are to provide a procedure for preparing these compounds; pharmaceutical compositions comprising an effective amount of these compounds; the use of the compounds for manufacturing a medicament for the treatment of pathological conditions or diseases that can improve by inhibition of at least one kinase selected from ARK5, JAK3 and TYK2, such as autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancer such as blood cancer, gastric cancer, colon cancer, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, breast cancer, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eye and allergic conjunctivitis, among others.
  • COPD chronic obstructive pulmonary disease
  • Protein kinases are enzymes that play key regulatory roles in nearly every aspect of cell biology. These enzymes participate in signal transduction modules that regulate apoptosis, cell cycle progression, cytoskeletal rearrangement, differentiation, development, the immune response, nervous system function and transcription. Protein kinases represent attractive drug targets because their dysregulation occurs in a variety of illnesses including cancer, diabetes autoimmune, cardiovascular, inflammatory and nervous disorders. ( Roskoski, R., Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes, Pharmacological Research 103 (2016) 26-48 ).
  • AMP-activated protein kinase is a protein kinase which has been found to be a master sensor and regulator of energy homeostasis. Its activity is regulated by increased intracellular AMP:ATP ratio in cells under metabolic stress (hypoxia, heat shock and ischemia).
  • ARKs AMPK-related kinases
  • NUAK1 novel (nua) kinase family
  • ARK5 is overexpressed in malignancies such as breast cancer, colorectal carcinoma, and hepatocellular carcinoma; patients with ARK5 overexpression often have poor prognosis.
  • ARK5 is an independent prognostic factor for overall survival in patients with hepatocellular carcinoma (HCC).
  • High expression of ARK5 in tumor is strongly correlated with tumor size, histological differentiation, and tumor-node-metastasis (TNM) stage.
  • TPM tumor-node-metastasis
  • ARK5 was found to be specifically required for the viability of cells overexpressing MYC, an oncoprotein that contributes to the genesis of many human tumors ( Liu et al, Deregulated MYC expression induces dependence upon AMPK-related kinase 5, Nature 2012, 483, 608 ). MYC function is closely associated with MYC levels, therefore ARK5 inhibition offers a therapeutic strategy to eliminate tumor cells that express deregulated MYC ( Li et al, MYC-mediated synthetic lethality for treating tumors, Current Cancer Drug Targets 2015, 15, 99-115 ).
  • JAKs Janus kinases
  • JAKs are a family of intracellular, nonreceptor tyrosine kinases which are important signal transducers of many cytokines, growth factors and interferon.
  • JAKs has been found that there is a significant enhancement in the expression of JAKs in cancer cells and cells transfected with oncogenes.
  • JAKs has a close relationship with inflammation and autoimmune diseases and immune rejection of transplants.
  • Aggarwal, B B et al Signal Transducer and Activator of Transcription-3, Inflammation, and Cancer How Intimate Is the Relationship? Ann. N.Y. Acad. Sci. 1171: 59-76 (2009 ) and references therein).
  • JAKs are a family of non-receptor tyrosine kinases that are relatively large molecules. There are four family members of JAKs: JAK1, JAK2, JAK3 and TYK2. JAK1, JAK2 and TYK2 exist in various tissues and cells, while JAK3 only exists in the marrow and lymphatic system. JAKs transmit extracellular stimuli through signals that are generated by the relevant receptors. Receptors and/or JAKs selectively activate signal transduction and signal transducer and activator of transcription (STAT) proteins by different phosphorylation sites. ( Jiang JJJ et al, Advances in the Inhibitors of Janus Kinase, Med Chem, 2014, 4: 540-548 and references therein).
  • JAK3 it is a key cell signalling molecule in the immune response, which is specifically distributed in the lymphatic system; in which interleukin-2 (IL2) can activate JAK3 within a very short period of time. After a period of signal transduction, JAK3 can dephosphorylate and become inactive, so that signals generating quenching facilitate the next round of stimulus signal transmission. Thus, the inhibition of JAK3 activity will prevent side effects caused by damage to other tissues.
  • Tofacitinib is a potent inhibitor of JAK3 and JAK1 with some activity against JAK2. It has been approved in several countries for the treatment of arthritis rheumatoid (RA), and is in advanced clinical phases for the treatment of patients with moderate-to-severe psoriasis.
  • RA arthritis rheumatoid
  • y Chiricozzi A et al, Tofacitinib for the treatment of moderate-to-severe psoriasis, Expert Rev. Clin. Immunol. Early online, 1-13 (2015 )).
  • Tofacitinib is also being investigated for the treatment of Crohn's disease, an inflammatory disease of the small intestine and colon characterized by alternating periods of relapse and remission, in patients with moderate-to-severe disease, although there were no significant differences in the percentage of patients with moderate-to-severe disease who achieved clinical responses after 4 weeks' administration of Tofacitinib or placebo. Therefore, additional studies are needed to determine whether Tofacitinib is effective for the treatment of Crohn's disease. ( Sandborn, W et al, A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients with Crohn's Disease, Current, Clin Gastroenterol Hepatol. 2014 Sep;12(9):1485-93 ).
  • JAKs inhibitors are in clinical phases for the treatment of psoriasis and RA, among others conditions.
  • One of them is the ASP015K (peficitinib), a selective JAK3 inhibitor, which is undergoing investigation for the treatment of moderate-to-severe psoriasis.
  • ASP015K peficitinib
  • JAK Inhibitors Treatment Efficacy and Safety Profile in Patients with Psoriasis, Journal of Immunology Research, Volume 2014, Article ID 283617, 7 pages
  • others selective JAK3 inhibitors such as VX-509 (decernotinib) are known.
  • VX-509 is in clinical phase for the treatment of RA
  • R348 is in clinical phase for the treatment of lupus erythematosus.
  • y Chiricozzi A et al, Tofacitinib for the treatment of moderate-to-severe psoriasis, Expert Rev. Clin. Immunol. Early online, 1-13 (2015 )).
  • TD-1473 is another potent JAK1, JAK2, JAK3, and TYK2 inhibitor at the human JAK kinase domains, which is considered a novel pan-JAK inhibitor, designed to inhibit JAK in the gastro intestinal (GI) tract upon oral dosing.
  • the compound has demonstrated a favourable safety and tolerability profile in the initial clinical trial in healthy volunteers, so is has planned phase 1b trial in patients, in order to develop a treatment for ulcerative colitis and other inflammatory intestinal diseases.
  • Beattie D et al, TD-1473 a novel, potent, and orally administered, GI-targeted, pan-Janus kinase (JAK) inhibitor, Therassemble Biopharma, South San Francisco, Poster presentations: Basic science (2016 )).
  • Tofacitinib is also being investigated for the treatment of Crohn's disease, an inflammatory disease of the small intestine and colon characterized by alternating periods of relapse and remission, in patients with moderate-to-severe disease, although there were no significant differences in the percentage of patients with moderate-to-severe disease who achieved clinical responses after 4 weeks' administration of Tofacitinib or placebo. Therefore, additional studies are needed to determine whether Tofacitinib is effective for the treatment of Crohn's disease. ( Sandborn, W et al, A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients with Crohn's Disease, Current, Clin Gastroenterol Hepatol. 2014 Sep;12(9):1485-93 ).
  • JAK3 JAK3 inhibition could lead to the prevention and treatment of diseases including ulcerative colitis, Crohn's disease, asthma, allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, eczema, psoriasis, allergic conjunctivitis and uveitis, among others.
  • diseases including ulcerative colitis, Crohn's disease, asthma, allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, eczema, psoriasis, allergic conjunctivitis and uveitis, among others.
  • diseases including ulcerative colitis, Crohn's disease, asthma, allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, eczema, psoriasis, allergic conjunctivitis and uveitis, among others.
  • TYK2 enzyme has demonstrated an important role for signalling transduction in response to a wide variety of cytokines, including type I IFNs, IL-6, IL-10, IL-12 and IL-23.
  • An appropriate expression of TYK2-mediated signalling might be essential for maintaining normal immune responses although in pathological conditions they promote the production of autoimmune-associated components, which are implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis.
  • Aberrant expression of TYK2 has been observed in many autoimmune conditions. ( Yan Liang et al, Therapeutic potential of tyrosine kinase 2 in autoimmunity, Expert Opin. Ther.
  • TYK2 remains the least explored member of this family. Only few disclosures claiming selective TYK2 inhibitors have been published to date and no TYK2-selective inhibitors are known to be in clinical trial. The only molecule claiming TYK2 inhibition currently in a clinical trial is a compound from Pfizer: pan-inhibitor PF-06263726 (topical, psoriasis). ( Menet C J, Toward selective TYK2 inhibitors as therapeutic agents for the treatment of inflammatory diseases, Pharm. Pat. Anal. (2014) 3(4), 449-466 ).
  • JAK2 due to its role in several physiological essential processes, such as erythropoiesis and neutrophil functions, to avoid its inhibition is particularly desirable.
  • the authors of the present invention have developed new 11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide derivatives as potent and selective inhibitors of protein kinases, specifically of at least one enzyme selected from ARK5, JAK3 and TYK2.
  • the present invention refers to novel 11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide derivatives of formula (I): wherein:
  • the present invention relates to processes for the preparation of the compounds of aspect 1.
  • the present invention relates to pharmaceutical compositions comprising a compound of aspect 1 and a pharmaceutical aspect diluent or carrier.
  • compositions according to the third aspect described above which further comprise a therapeutically effective amount of a therapeutic agent selected from agent useful for the treatment of autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancers such as blood cancer, gastric cancer, colon cancer, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, breast cancer, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eye and allergic conjunctivitis, among others.
  • autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancers
  • the present invention relates to the use of the compound of aspect 1 in the manufacture of a medicament for the treatment of a disease or pathological condition that can be ameliorated by inhibition of at least one enzyme selected from ARK5, JAK3 and TYK2, such as autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancer such as blood, gastric, colon, colorectal, liver, lung, pancreatic, breast, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eyes and allergic conjunctivitis, among others.
  • COPD chronic obstructive pulmonary disease
  • the present invention relates to methods for the treatment of diseases that can be ameliorated by inhibition of at least one enzyme selected from ARK5, JAK3 and TYK2 by administration of the compounds of the first aspect or pharmaceutical compositions of the second or third aspects described above to a subject in need of said treatment;
  • the diseases are selected from autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancer such as blood cancer, gastric cancer, colon cancer, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, breast cancer, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eye and allergic conjunctivitis, among others.
  • COPD chronic obstructive pulmonary disease
  • the present invention relates to a combination product of the compound of the first aspect described above with one more therapeutic agent known to be useful in the treatment of diseases selected from such as autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancer such as blood cancer, gastric cancer, colon cancer, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, breast, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eye and allergic conjunctivitis, among others.
  • diseases selected from such as autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis
  • the present invention relates to the compound of aspect 1 for use in the treatment of a disease or pathological condition that can be ameliorated by inhibition of at least one enzyme selected from ARK5, JAK3 and TYK2, such as autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancer such as blood, gastric, colon, colorectal, liver, lung, pancreatic, breast, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eye and allergic conjunctivitis, among others.
  • COPD chronic obstructive pulmonary disease
  • the 11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide derivatives of the invention are useful in the treatment or prevention of diseases known to be susceptible to amelioration by treatment with inhibitors of at least one enzyme kinases selected from ARK5, JAK3 and TYK2 such as autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancer such as blood, gastric, colon, colorectal, liver, lung, pancreatic, breast, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eye and allergic conjunctivitis, among others.
  • COPD chronic obstructive pulmonary disease
  • the compounds of formula (I) due to their low to moderate systemic exposure after oral administration and consequently a lower risk of causing side effects, are especially suited for the topical/local treatment of diseases such as, for example, psoriasis, atopic dermatitis, alopecia areata, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, asthma, chronic obstructive pulmonary disease (COPD), uveitis, dry eye and allergic conjunctivitis.
  • diseases such as, for example, psoriasis, atopic dermatitis, alopecia areata, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, asthma, chronic obstructive pulmonary disease (COPD), uveitis, dry eye and allergic conjunctivitis.
  • COPD chronic obstructive pulmonary disease
  • the derivatives of the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and / or salts thereof may be used in a method of treatment of pathological conditions or disease of human body which comprises administering to a subject in need of said treatment, an effective amount of the 11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide derivative of the invention or a pharmaceutically acceptable salt thereof.
  • C a -C b cycloalkyl embraces hydrocarbon cyclic groups having a to b carbon atoms.
  • Such cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C a -C b alkyl includes linear or branched hydrocarbon radicals, having from a to b carbon atoms. Preferred radicals include 1 to 4 carbon atoms. Examples of linear or branched alky groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, i-butyl, sec-butyl, tert-buty, pentyl and hexyl.
  • linear or branched C a -C b alkoxy is used to designate radicals which contain linear or branched C a -C b alkyl radicals linked to an oxygen atom (C x H 2x+1 -O-).
  • Preferred alkoxy radicals include, for example, methoxy, ethoxy, n-propoxy, i-propoxy.
  • C a -C b heterocyclic ring embraces a saturated or unsaturated ring having a to b carbon atoms and at least a heteroatom selected from N, O and S forming part of the ring.
  • Such heterocyclic ring includes, for example, pyridinyl, pyrimidinyl, pyperazinyl, furyl, thienyl, pyperazinyl, morpholinyl.
  • Preferred radicals are optionally substituted pyridinyl, pyperazinyl and morpholinyl group.
  • Said heterocyclic rings are optionally substituted by 1, 2 or 3 substituents selected from halogen atom, C 1 -C 6 alkyl linear or branched and C 1 -C 4 alkoxy linear or branched.
  • the substituents of the heterocyclic ring may be replacing a hydrogen atom of any of the carbon atoms in the ring or a hydrogen atom of any of the nitrogen atoms in the ring.
  • halogen atom includes chlorine, fluorine, bromine and iodine atoms, preferably fluorine, chlorine and bromine atoms.
  • halo when used as a prefix, has the same meaning.
  • a 5- to 10- membered, saturated, cycle embraces ring systems of 5-to 10 members containing carbon atoms and optionally 1 or 2 heteroatoms selected from N and O.
  • Said ring systems may be monocyclic or polycyclic and the polycyclic ring system include systems with fused rings (i.e. rings sharing two ring atoms), bridged rings (i.e. rings sharing more than two ring atoms) and spiranic systems (i.e.
  • Said cycles include, by way of example, the following monocyclic ring systems: cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, and piperidinyl, and the following polycyclic bridged ring systems: bicyclo[2.2.1]heptanyl, bicyclo[2.2.2] octanyl 7-aza-bicyclo[2.2.1]heptanyl and adamantyl.
  • Said cycles are optionally substituted by 1, 2 or 3 substituents selected from C 1 -C 6 alkyl linear or branched, C 1 -C 6 alkoxy linear or branched, -OH and amines.
  • the substituents of the 5- to 10- membered cycle may be replacing a hydrogen atom of any of the carbon atoms in the cycle or a hydrogen atom of any of the nitrogen atoms in the cycle.
  • the 5- to 10- membered, saturated, polycyclic ring systems comprise two or more fused or bridged rings each consisting of 3 to 7 atoms, wherein 1 or 2 atoms can be heteroatoms selected from N and O.
  • atoms, radicals, chains or cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, chains or cycles can be either unsubstituted or substituted in any position by one or more, for example 1, 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, chains or cycles are replaced by chemically acceptable atoms, radicals, chains or cycles. When two or more substituents are present, each substituent may be the same or different
  • the term pharmaceutically acceptable salt is used to designate salts with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium), alkali earth metal (e.g. calcium or magnesium) hydroxides, and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.
  • X -n may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulphonate.
  • X -n is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X - is chloride, bromide, trifluoroacetate or methanesulfonate.
  • R 1 represents a group selected from:
  • R 1 represents a group selected from:
  • R 1 represents cyclopropyl group optionally substituted by a group selected from linear or branched C 1 -C 6 alkyl and linear or branched C 1 -C 4 alkoxy.
  • R 3 represents a 5- to 10- membered saturated monocyclic ring system containing carbon atoms and optionally 1 or 2 heteroatoms selected from N and O.
  • R 3 represents a 5- to 6- membered saturated cycle optionally containing one oxygen atom and which is optionally substituted by a group selected from linear or branched C 1 -C 6 alkyl and -OH.
  • R 3 represents a group selected from cyclopentyl and cyclohexyl group optionally substituted by one group selected from linear or branched C 1 -C 6 alkyl and -OH.
  • R 4 and R 5 represent a hydrogen atom.
  • R 1 represents a group selected from, methoxy group, cyclopropyl group optionally substituted by a group selected from linear or branched C 1 -C 6 alkyl and linear or branched C 1 -C 4 alkoxy and six-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N and O and which is optionally substituted by a group selected from linear or branched C 1 -C 6 alkyl
  • m and n have a value of 0
  • R 3 represents a group selected from cyclopentyl and cyclohexyl group optionally substituted by one group selected from linear or branched C 1 -C 6 alkyl and -OH.
  • R 1 represents a group selected from six-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N and O and which is optionally substituted by a group selected from linear or branched C 1 -C 6 alkyl
  • m and n have a value of 0,
  • R 3 represents a group selected from cyclopentyl and cyclohexyl group optionally substituted by one group selected from linear or branched C 1 -C 6 alkyl and -OH.
  • R 1 represents a cyclopropyl group optionally substituted by a group selected from linear or branched C 1 -C 3 alkyl and linear or branched C 1 -C 2 alkoxy
  • n and m have a value of zero
  • R 3 represents a cyclohexyl group optionally substituted by a group selected from linear or branched C 1 -C 3 alkyl and -OH.
  • Particular individual compounds of the present invention include:
  • compounds of formula (I) are compounds according to the present invention wherein R 1 , R 2 , R 3 and R 6 are as hereinabove defined.
  • Derivatives of general formula (V) are prepared from commercially available optionally substituted 2-aminobenzic acids or ethyl or methyl optionally substituted 2-aminobenzoates or the correspondent optionally substituted amino-heteroaryl carboxylates (III) and optionally substituted 2-chloronicotinic acid or optionally substituted chlorheteroarylic acids (IV), according to Scheme 1.
  • that reagent (III) are not available, it can be obtained, for example, through the substitution of the bromide atom from the corresponding carboxylic acids or carboxylate derivatives of formula (II).
  • the starting reagents (III) and (IV) are reacted by a cyclization reaction in acidic condition in isopropanol, dioxane or xylene at temperatures between 80o and 110oC to provide acids of formula (V).
  • the reaction of these acids with amines (VI) in polar aprotic solvents such as DCM, THF, Acetonitrile or DMF in the presence of coupling reagent such as HATU, EDC, HOBt or T3P and temperatures ranging from 0oC to 80oC provides compounds of formula (I), which are the object of the present invention.
  • substituted compounds of formula (I) is achieved, for example, through the nucleophilic substitution of brominated derivatives (VII) and (VIII) with amines or through the coupling reaction of these derivatives, for instance with aryl or heteroaryl boronic acids under Suzuki conditions according to scheme 2.
  • Such compounds of formula (Ia) and (Ib) are particular cases of the present invention.
  • compounds of formula (I) are compounds according to the present invention wherein R 1 , R 2 , R 3 and R 6 are as hereinabove defined.
  • the functional assays of protein Janus kinases were carried out in 384-well plates using a final volume of 30 ⁇ l.
  • the reaction begins through the combination between the kinase enzyme and the peptic substrates (indicated in the table wherein the prefix 5-FAM indicates that the amino terminal group of the peptide is linked to 5-carboxyfluorescein and CONH 2 indicates that the carboxylic acid terminal group is amidated) in a concentration of 1.5 ⁇ M in presence of ATP and non-ATP controls.
  • the reaction was reads in a "Caliper EzReader LabChip 3000" (Caliper, Hopkinton, MA) reader, based on electrophoretic mobility of the fluorescent substrate and the phosphorylated product.
  • the inhibition percentages were calculated by comparison between control reactions, for 100% of inhibition and reactions with only DMSO for 0% of inhibition.
  • Activity test was carried out using the kit from Reaction Biology (CAT#: ARK5/NUAK1).
  • the test uses enzyme Human ARK5/NUAK1 and the substrate is the peptide KKKVSRSGLYRSPSMPENLNRPR (SEQ ID NO: 1), 20 ⁇ M and ATP 10 ⁇ M.
  • Other reagents are the following: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO.
  • reaction was carried out following the instructions of manufacturer. Briefly, kinase/substrate pairs were prepared in reaction buffer. Compounds were delivered into the reaction, followed 20 minutes later by addition of a mixture of ATP (Sigma, St. Louis MO) and 33 P ATP (Perkin Elmer, Waltham MA) to a final concentration of 10 ⁇ M. Reactions were carried out at room temperature for 120 min, followed by spotting of the reactions onto P81 ion exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by extensive washing of filters in 0.75% phosphoric acid.
  • ATP Sigma, St. Louis MO
  • 33 P ATP Perkin Elmer, Waltham MA
  • kinase activity data was expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. IC 50 values and curve fits were obtained using Prism (GraphPad Software).
  • Table 1 shows how various compounds of the present invention score in a three-level classification according to their enzymatic activity (IC 50 ) values.
  • Table 1 Ex. Compound ARK5 JAK1 JAK2 JAK3 TYK2 1 N-cyclohexyl-2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide A C C A A 2 N-cyclopentyl-2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide A C C A A A 3 2-cyclopropyl-N-(1-methylpiperidin-4-yl)-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide - C C B C 4 2-cyclopropyl-11-oxo-N-(tetrahydro-2H-pyran-4-yl)-11H-pyrido[2,1-b]quin
  • a compound is assigned score A when its IC 50 is lower than 100 nM
  • a compound is assigned score B when its IC 50 ranges between 100 nM and less than 1 ⁇ M.
  • a compound is assigned score C when its IC 50 is greater than 1 ⁇ M).
  • the compounds of the present invention are potent inhibitors of at least one kinases selected from ARK5, JAK3 and TYK2, showing good selectivity against the enzymes JAK1 and JAK2.
  • the derivatives of the invention are useful in the treatment or prevention of diseases known to be susceptible to improvement by treatment with an inhibitor of at least one protein kinase selected from ARK5, JAK3 and TYK2.
  • diseases are autoimmune diseases including psoriasis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, alopecia areata, lupus, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, cancer such as blood cancer, gastric cancer, colon cancer, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, breast cancer, and other solid tumours, and others diseases such as asthma, chronic obstructive pulmonary disease (COPD), transplant rejection, haematological disease, uveitis, dry eye and allergic conjunctivitis, among others.
  • COPD chronic obstructive pulmonary disease
  • the derivatives of the invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and/or salts thereof may be used in a method of treatment of disorders of the human body which comprises administering to a subject requiring such treatment an effective amount of the 11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide derivatives of the invention or a pharmaceutically acceptable salt thereof.
  • the present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a 11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide derivatives of formula (I) or a pharmaceutically acceptable salt thereof in association with, others therapeutics agents a pharmaceutically acceptable excipient such as a carrier or diluent.
  • the active ingredient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% by weight of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.
  • compounds of formula (I), pharmaceutically acceptable salts and compositions thereof are made up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration.
  • compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.
  • compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
  • diluents which may be used in the preparation of the compositions, include those liquid and solid diluents, which are compatible with the active ingredient, together with colouring or flavouring agents, if desired.
  • Tablets or capsules may conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof.
  • the liquid composition adapted for oral use may be in the form of solutions or suspensions.
  • the solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form syrup.
  • the suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
  • compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in pyrogen free aqueous media or other appropriate parenteral injection fluid.
  • Effective doses are normally in the range of 2-2000 mg of active ingredient per day.
  • Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
  • the HPLC-MS were performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1/1000 Gilson splitter, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fennigan aQa detector.
  • Example 12 2-cyclopropyl-N-((1S,2S)-2-hydroxycyclohexyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide

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EP18759146.6A 2017-06-01 2018-05-31 Pyridoquinazoline derivatives useful as protein kinase inhibitors Active EP3632912B1 (en)

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RS20210545A RS61833B1 (sr) 2017-06-01 2018-05-31 Derivati piridohinazolina korisni kao inhibitori proteinske kinaze
SI201830289T SI3632912T1 (sl) 2017-06-01 2018-05-31 Derivati piridokinazolina, primerni kot zaviralci proteinske kinaze
PL18759146T PL3632912T3 (pl) 2017-06-01 2018-05-31 Pochodne pirydochinazoliny użyteczne jako inhibitory kinaz białkowych
HRP20210814TT HRP20210814T1 (hr) 2017-06-01 2021-05-20 Derivati piridokinazolina korisni kao inhibitori proteinskih kinaza

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US4551460A (en) 1982-05-10 1985-11-05 Hoffmann-La Roche Inc. Pyrido[2,1-b]quinazoline derivatives useful as agents for treatment of allergic conditions and vascular disorders involving thrombosis
AU5465198A (en) * 1996-11-26 1998-06-22 American Cyanamid Company Hetero-biaryl-pyridoquinazolinone derivatives as anti-cancer agents
US20050171172A1 (en) * 2003-11-13 2005-08-04 Ambit Biosciences Corporation Amide derivatives as PDGFR modulators
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WO2010061971A1 (ja) 2008-11-28 2010-06-03 興和株式会社 ピリジン－３－カルボキシアミド誘導体
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SI3632912T1 (sl) 2021-08-31
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US20200148676A1 (en) 2020-05-14
BR112019024892A2 (pt) 2020-06-16
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CN111247143B (zh) 2022-07-05
EP3632912A1 (en) 2020-04-08
AU2018278283A1 (en) 2019-12-19
HUE054792T2 (hu) 2021-09-28
ZA201908372B (en) 2021-04-28
WO2018220252A1 (es) 2018-12-06
ES2881960T3 (es) 2021-11-30
PT3632912T (pt) 2021-06-02
MX2019014436A (es) 2020-02-10
CN111247143A (zh) 2020-06-05
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RS61833B1 (sr) 2021-06-30
CY1124087T1 (el) 2022-05-27
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HRP20210814T1 (hr) 2021-06-25
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